This application seeks renewed support for MH 59803, "Dopaminergic substrates of startle gating across species". For 20 years, systematic studies in rodents have identified specific neural substrates regulating prepulse inhibition (PPI) of startle. These limbic cortico-striatal-pallido-pontine (CSPP) substrates regulating PPI are relevant to several neuropsychiatric disorders, and are implicated in the reinforcing properties of drugs of abuse. Now that the neural substrates of PPI have been delineated in rats, the next major challenge is to develop the capacity to probe and understand this PPI-regulatory circuitry in humans. If neural circuit information, derived from animal studies, could be translated across species, PPI could become an important, new tool for understanding this circuitry in normal and neuropsychiatric disordered populations MH 59803 began this process, by characterizing the effects of dopaminergic manipulations on PPI and related measures in normal men. The present proposal extends this translational approach to assess both NMDA antagonist and dopamine (DA) agonist and antagonist effects on gating measures in normal men and women. In tests of PPI, sensory gating and latent inhibition, studies will carefully assess the effects of NMDA antagonists (Aim 1: amantadine, memantine) and dopamine agonists (Aim 3: pramipexole) in normal men. Contemporaneous physiological and psychological measures will facilitate interpretation of changes in the critical dependent measures. Based on initial results, studies will assess NMDA antagonist effects on the dependent measures after pretreatment with typical and atypical antipsychotics (Aim 2: perphenazine, quetiapine). Studies using the most effective NMDA antagonist and DA agonist will also be pursued in normal women, to verify that the predicted neurochemical substrates of PPI apply to humans of both sexes (Aim 4). Data from the proposed studies will provide information for interpreting the neurochemical basis of PPI deficits in schizophrenia patients, as well as the sensitivity of these deficits to antipsychotics. By developing an important new strategy for understanding limbic CSPP circuitry in humans, the proposed studies will have direct relevance to a broad range of issues in neuropsychiatry, including the neurobiology of drug abuse. More generally, these studies will leverage findings from MH 59803 years 1-5, to extend the important process of examining the neurochemistry of sensorimotor gating processes that fundamentally shape behavior and cognition in humans.